what’s happening on the ground in MI. He explains that the law is changing and in the long-term that will be a good thing. He and his colleagues are suffering through what should be short-term raids in the time being. As you’ll hear though, the timeline is certainly up for interpretation.

Dr. David Schubert then joins us to discuss his work with cannabis and Alzheimer’s and what led him to a molecular biology approach to how the brain works and his overall work in neuroscience. Dave dealt with the initial misconception that the brain could be easily understood and he explains that for the most part, we still don’t understand it. That said, David does have some answers…which he shares. Prof Schubert also sheds light on the way that way that drug discovery works…or doesn’t.

Transcript:

Speaker 1: Dr Dave Schubert and Jamie Lowell Jamie lowell returns to give us an update on what's happening on the ground in Michigan. He explains that the laws changing and in the long term this will be a good thing he and his colleagues are suffering through what should be short term rates in the time being. As you'll hear though, the timeline is certainly up for interpretation. Dr Dave Schubert then joins us to discuss his work with cannabis and Alzheimer's and what led him to a molecular biology approach to how the brain works in his overall work in neuroscience. They've dealt with the initial misconception that the brain could easily be understood and he explains that for the most part, 50 years later, we still don't understand it. That said, Dave does have some answers which he shares. Professors Schubert also sheds light on the way that drug discovery works or doesn't welcome to cannabis economy. I'm your host Seth Adler. Check us out on social with the handle can economy. That's two ends of the word economy. Jamie lol. And then Dr Dave Schubert

Speaker 3: Well, there's a lot of changes taking place in Michigan concerning distribution of medical marijuana. The state finally accurate. It passed two laws. So with that in that transitionary time, uh, there's some upheaval and some misunderstanding, different interpretations and all those things that commonly come up, law change and there's some raids and uh, an action like that and it's still working it out. And in addition to that, there are other efforts taking place in sort of changing these new log already before they really get implemented in one way or the other. People fighting over how that policy is going to work. So, uh, there is some positive movement and recognition of things, but that really smoothing it out and getting everybody on the same page and how it's going down. It's a rough thing. It's not uncommon, but it's really our income

Speaker 2: understanding that the new law as the ability to change what is, uh, what is written, what is true now that, uh, that wasn't necessarily a few months ago

Speaker 3: for commerce and businesses to be recognized on a state level and have kind of statewide brand, but are there still a local component in which the local community has to want that and which way, where they're going to be resolved and all that kind of stuff. And then once that's established, there's a statewide process which there are a, the application for license Ford and the approval of an athletic thing. Um, and so once that somebody were able to complete that process, say what, that'd be recognized on a statewide level, whereas that was never before the case for expenses were either kind of renegade forehead, just local acceptance or approval.

Speaker 2: So there in lies the rub if we're still in the process of gaining, you know, the blessing from the state. Uh, that's why the ranger happening. Is that about right?

Speaker 3: Yeah, they've gone on continuously at different times, but right now with this pending new system coming, I'm sure, uh, some of those agencies and taskforce and feel a little bit more empowered to move forward in December 20th. The law read that if you're doing these type of distribution and tried a lot of place without a proper license, enforceable.

Speaker 2: And what do you do if this is your job, if this is your business, in other words, you know, you kind of got to keep it open, right? While you, while you apply.

Speaker 3: I had three different things while this process continues with the new legislation or to establish all the components necessary to have people licensed, recognize on a statewide level and that type of thing. As long as there's local tolerance, it's almost like as if it's before this, I mean at least for that small period of time, it's all the same questions are in place, all the same legality to replace. So as long as you have a friendly area, you'll see some things just kinda continue on as normal, at least for the next thing is those places who are operating, they're typically already have local approval, so now they need the next day. So like part of the job's already done and she started working towards figuring out how the statewide process is going to be and you start looking at that, uh, spent a third thing is that you try to go above all that and you know, working on a statewide initiative or do some other heavy lobbying. So where else in order to slay policy in order to kind of clarify things in a manner that make it easier to stay put, things are going up.

Speaker 1: Dr Dave Schubert and Jamie Lowell Jamie lowell returns to give us an update on what's happening on the ground in Michigan. He explains that the laws changing and in the long term this will be a good thing he and his colleagues are suffering through what should be short term rates in the time being. As you'll hear though, the timeline is certainly up for interpretation. Dr Dave Schubert then joins us to discuss his work with cannabis and Alzheimer's and what led him to a molecular biology approach to how the brain works in his overall work in neuroscience. They've dealt with the initial misconception that the brain could easily be understood and he explains that for the most part, 50 years later, we still don't understand it. That said, Dave does have some answers which he shares. Professors Schubert also sheds light on the way that drug discovery works or doesn't welcome to cannabis economy. I'm your host Seth Adler. Check us out on social with the handle can economy. That's two ends of the word economy. Jamie lol. And then Dr Dave Schubert

Speaker 3: Well, there's a lot of changes taking place in Michigan concerning distribution of medical marijuana. The state finally accurate. It passed two laws. So with that in that transitionary time, uh, there's some upheaval and some misunderstanding, different interpretations and all those things that commonly come up, law change and there's some raids and uh, an action like that and it's still working it out. And in addition to that, there are other efforts taking place in sort of changing these new log already before they really get implemented in one way or the other. People fighting over how that policy is going to work. So, uh, there is some positive movement and recognition of things, but that really smoothing it out and getting everybody on the same page and how it's going down. It's a rough thing. It's not uncommon, but it's really our income

Speaker 2: understanding that the new law as the ability to change what is, uh, what is written, what is true now that, uh, that wasn't necessarily a few months ago

Speaker 3: for commerce and businesses to be recognized on a state level and have kind of statewide brand, but are there still a local component in which the local community has to want that and which way, where they're going to be resolved and all that kind of stuff. And then once that's established, there's a statewide process which there are a, the application for license Ford and the approval of an athletic thing. Um, and so once that somebody were able to complete that process, say what, that'd be recognized on a statewide level, whereas that was never before the case for expenses were either kind of renegade forehead, just local acceptance or approval.

Speaker 2: So there in lies the rub if we're still in the process of gaining, you know, the blessing from the state. Uh, that's why the ranger happening. Is that about right?

Speaker 3: Yeah, they've gone on continuously at different times, but right now with this pending new system coming, I'm sure, uh, some of those agencies and taskforce and feel a little bit more empowered to move forward in December 20th. The law read that if you're doing these type of distribution and tried a lot of place without a proper license, enforceable.

Speaker 2: And what do you do if this is your job, if this is your business, in other words, you know, you kind of got to keep it open, right? While you, while you apply.

Speaker 3: I had three different things while this process continues with the new legislation or to establish all the components necessary to have people licensed, recognize on a statewide level and that type of thing. As long as there's local tolerance, it's almost like as if it's before this, I mean at least for that small period of time, it's all the same questions are in place, all the same legality to replace. So as long as you have a friendly area, you'll see some things just kinda continue on as normal, at least for the next thing is those places who are operating, they're typically already have local approval, so now they need the next day. So like part of the job's already done and she started working towards figuring out how the statewide process is going to be and you start looking at that, uh, spent a third thing is that you try to go above all that and you know, working on a statewide initiative or do some other heavy lobbying. So where else in order to slay policy in order to kind of clarify things in a manner that make it easier to stay put, things are going up.

Speaker 2: You mentioned a couple of months, what kind of timeline is there, what, where are the deadlines, where is the timeline

Speaker 3: that actually goes into effect December 20th. And with it comes some good things. But also with it comes with very questionable things. According to the law, there are three other 60 days before or in order to get ready to issue licenses on a statewide level. So presumably you work a lot during that time, a local stuff and get multiple approval, how they are going to do a write an origin for these things and there are five different things at play they can choose to have some or none of them. And so

Speaker 2: what are some of the five,

Speaker 3: uh, a testing lab as the transportation company? A, a, a like a manufacturing lab or we're a extracts and edibles and things like that are made a growing probation and the retail side of it.

Speaker 3: In some ways it sounds like it, but I, you know, my personal opinion, the restrictions are such, and the process is such that it gets away from a functionality and efficiency and still keeps a lot of room open for police enforcement against people. And it's a central address. A lot of things that we would ideally like brought. It does, it does recognize this activity takes place. Like all laws. They can be changed and amended. One concern it. So, you know, that's just where we are. I, I don't prefer it particularly in legislature passing it. It's kind of a red flag in some ways given our history on this issue. Um, so it was the plane, but there are positives and, and, um, you know, to draw those out and utilize those people stepped up because it's real. They were here, this is what we have to work with right now.

Speaker 2: So if December 20th is that first date, when do you sense it being, you know, kind of, uh, you know, you hitting all of your goals and making sure to do what is needed. When do you sense it? Kind of calming down if you will,

Speaker 3: 360 day period. Now some people are interpreting the statewide process. So that's the kind of timeframe if you have any huge change in that thing and some people are saying no, these panels are being worked on right now and there's fighting over influence if we get on and all that kind of stuff. And some people are saying that the makeup of them are looking actually quite reasonable compared to what some of the concerns are the ad which is, which is good news if that turns out to be true set. See other interpretation is it just means that you have that long to put this in place and if you get it in place sooner than the process can start sooner and some people are saying that it is already underway and by spring we'll be positioned on a statewide level. So if that's the case and that kind of timeframe is short and so, so the, so these are waiting seat by thing.

Speaker 2: It does sound a lot like I said, um, but, uh, but you're wading through it. And, and I love the fact, uh, you are also thinking about mia legalized still to this day and uh, you know, you're looking down the barrel of what's next on, on Emi legalize. Yeah.

Speaker 3: So the initiative process and the other way to help get things established that make more sense or that would be an improvement upon the beginning that we were given here and legalized second time around the first time around. I'm on the board and I'm very biased and very big part of it. Uh, so. So my opinion, you were unconstitutionally denied bail. So fighting federal federal court right now. So they will be some resolution or some needs there, maybe not. We're not relying on that, although we're still gonna fight really hard there and expect somebody to look into that. A undo burden and a voter disenfranchisement or things the federal government has taken an interest in. So that's what our issues are slogan that we get somewhere we can't stand still. So we're going forward again this time around. You have all the resources from last night.

Speaker 3: He have time now before we actually start gathering signatures to put our strategy and to raise the money that we need. Uh, so those, those are things that we're working on. We're aware of national organizations looking at digitalization of Michigan as well and they've been, you know, these are good organizations have been successful in other state. And so we're looking at that combination of preserving the things that we've been working for and working with these organizations to have a unified, uh, a thompson probably be very successful, but she was very right in 2018. That's why they're looking for. And the more thinking and action we can take along those lines, the more successful it will likely be. And then that would that be the clarity that is in the law and we've worked from there. So this whole process, we're going to take a while before anything that those of us in the bubble, I think it's fine to be absolutely ideal. There'll be years before we get there, but we could really make some great progress here in the short term.

Speaker 2: I love it man. You just. You keep fighting. You wake up every day and you're not taking no for an answer. Is that about right

Speaker 3: at the right? I mean it's so surreal to be shut out the facts, the reason, the law on your side and just wants to shut you out. And so that didn't kill that motivated her and other people saw that too and they want to know a lot of people don't even have a big dog in the fight over cannabis policy. They don't like people having rights to do a rectify injustice. So they find helping us out now rectifying the injustice, the bus hitting a shut out of being on the ballot last time around. So we had a nice little grassroots, a story to tell that really gained some support and understanding of what's going on and get the outside of the cannabis people do

Speaker 2: with a little chip on your shoulder.

Speaker 3: Yeah. We're bringing the voice of democracy back to the states, back to the people instead of just through the legislative system, which has been no left wanting. When it addresses these issues and it gets them, it gets some people unified and fire it up and want to help out.

Speaker 2: I love it. All right, well we'll keep checking back with you. Uh, as a final question, I'll ask you the, a soundtrack, the soundtrack of your life. One track one song that's got to be on there today.

Speaker 3: Familiar with rush and freewill

Speaker 2: short. Well, I am familiar with Raj. I don't know if I know that track.

Speaker 3: It has a particular title is different than that. I will choose.

Speaker 2: Oh yeah. No, I know. That's fair enough. That's A. No,

Speaker 3: I don't care what else was going on and I know what my path is, what I'm working on, and we're focused over here and we're not going to let any other tell us that we can't accomplish the things that we need to accomplish.

Speaker 2: I love it, man. Jamie Lowell, thanks so much. Keep fighting. We'll check back in with you. How about that?

Speaker 3: Thanks. I appreciate it. Have a good day.

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Speaker 4: David Schubert, Professor David Schubert could call you Dr David Schubert if I wanted to achieve but not necessary, dave as Dave Davis.

Speaker 1: All right? Uh, so from the salt

Speaker 4: institute and is this a because of Jonas? Yes. So institute founded about 55, 60 years ago and fight join us all the time just after he discovered the polio vaccine.

Speaker 1: Yes. And we thank him for that. That's for sure. Uh, he, he, he then discovered the University of what was, uh, what was the point, what was the thinking behind, you know, okay, great. I found

Speaker 4: this wonderful cure. Let's keep going, type of thing. I think that's exactly right. I think he just wanted to assemble the best scientists in the world at that time into one place and there was a lot of input from people in France and the United States and they tried to get these top rate, absolute best scientists in the world in one place and try to solve some of the major problems that the world at that time of medical problems. Any chose southern California. Yes. There was a debate where to go. Um, they ended up in San Diego. Okay. Fortunately for us and the people that work there, fortunately you up, unfortunately, fortunately because it's beautiful there. Yes. Spectacular place. So not only do you get to really do this kind of next level research, which we'll get into, but you also get to, you know, kind of go to work in a basking in the sun.

Speaker 4: Yes. Our lab, half of the people serve everyday. So it's. Are you one of those surfers are used to be [inaudible] no longer now. Are you from Southern California? No, I'm from Indiana with them. What are you doing surfing? I'm one of the reasons I came out here. I actually went to a UC SD and San Diego is one of the first graduate students there. And uh, the goal was to learn to surf. I actually, I had a couple of choices where to go for graduate school and I saw a surfing magazine at Indiana University and the comments and I thought this is a place to go. And so we actually started at scripps oceanography right on the beach and uh, [inaudible] Graduate School at ucf was not built at that time. So we got onto it at the, because we don't have any buildings. Edifices, um, the ucs as text, is that right?

Speaker 4: State CCSD is, I don't know what they are. Trojans, I think. Okay. Fair enough. Uh, and so, so here's this guy from Indiana surfing. Did you, did you figure it out? Oh, we're good. Pretty good. All right. Yeah, for many years. Catching waves. That's right. Yeah. I just was telling someone else that uh, I tried to surf and I'm not really an athlete. Um, and the ocean let me know that I wasn't going to be a surfer either. It's difficult. It's one of the most difficult sports for sure. Because it. And how do you see, are you battling the ocean or you kind of going with whatever the ocean provides? How, how, what's the relationship between surfer and ocean? Um, it depends on how good you are. If you're for many months, if not years to start with, you're battling and then once you get good at your, you're, you're with it all.

Speaker 4: Alright. So, so graduate school in in San Diego. But what were you doing Undergrad in Indiana? Um, I was very fortunate. I started off just after high school, working in labs there. So I had a degree in chemistry in bacteriology that I had a chance to go to several graduate schools and I chose a university of California San Diego because of the reasons I just explained to you in part. And the other part is that, uh, I had a chance to work at the sulk institute because the graduate students at UC SD, you can work at Sol. Could I was the first one to do that and that was very fortunate. So you, I mean, you've, before they had buildings before they had a kind of postdocs, uh, you, you were, you were there. I was the first one. Yeah. Yeah. And I'm the one. So we, we appreciate, uh, you forging this path, right?

Speaker 4: Right. But you had science in your blood. It sounds like you were doing that. Did you know that when from when you were a kid that you were going to kind of grow up and be a scientist? I think so. I was very fortunate, um, my high school science teacher, Bill Smith was a fantastic person and I think a lot of scientists get involved in science and I said because of those teachers and I fortunately had a high school biology teacher who was incredibly good and got me interested in that high school science projects and whatever. So Saul about those teachers, isn't it? It is to try something. It's not appreciated how important they are. What have you noticed being a professor before we get down to the science I'm in as you've gone here, the change in the, uh, in the type of student that you have?

Speaker 4: I think the students are pretty much the same. The problem is that there are too many of them and it's, it's a, it's a difficult situation now for people who are graduating with degrees in chemistry or biology because the job market's very limited. Uh, and uh, I actually don't recommend people going into science. So unless you're absolutely passionate about it because it is so difficult to get jobs. Interesting. Alright. So, so you get a job at sulk. What, when you were 20? I mean, I've been really, I've been there for 50 years, 50 years. Fifty years, over 50. Congratulations. You look great. Thank you. I mean you've got to be over 50 is what, uh, you know, the math implies. No, I'm 73. So you look fantastic. Come on full head of hair. Walked over here from the other hotel. I'm lucky. Good genes. Exactly. So let's get to it.

Speaker 4: When you first started at salt, what, what, what did you first start to kind of research where, where was your mind and where were they as far as using you? Well, I started off working on immunology projects because my thesis advisor was a world famous immunologist and then we were very lucky at soc. We got people from Harvard to come in the summer too. They basically moved their labs. See coogler was very famous, um, a neurobiologist from Harvard and he liked to move his lab in the summer, so he started coming to silicon with summer and I took, he gave courses and I worked a little bit with some of his people and I started getting interested in neuroscience. Was his name again, just Steve Cooler, cooler. Okay. And he's long deceased, but he was a fantastic scientist that era, the sixties. And um, anyway, I got interested in neuroscience and I did a postdoc at, in Paris, which was again very lucky and came back and said where he started the neuroscience program itself.

Speaker 4: Okay. So is that, uh, you know, you, you start that, um, uh, that program. Um, and what were the first kind of things that you were working on once you came back from Paris, which we'll talk about hopefully, but maybe not the first thing my thesis was on. I'm trying to simplify the immune system by looking at a cell lines. Things that you can grow in tissue culture rather than studying the whole animal. And the idea at that time was you can do the same thing with a brain and try to understand what's going on in their brain by isolating ourselves from the brain is setting these individual cells and they, how they connect with each other and so on. So we've spent. I spent probably the first 10 years of my career at solid and I started on the faculty. I'm working on these cell lines that we made from the brain and trying to understand how nerves connect with bustle, how connected with each other they interacted, and Irvin glial cells and different components of the brain.

Speaker 4: So it was basically a of molecular biology approach to understanding how the brain works in a very simple system. So a new way of looking at how the brain works, right? And what work, uh, initial key findings based on the fact that you're, hey, here's the human brain. I'm looking at it a completely different way. Here's what I now know based on looking at it that way. Well, I think one of the things was that people didn't realize how complicated the individual cells were because people thought that no, the way that brain cells talk to each other, they only made one molecule. It's connected with the other cells. It's formed synopsis a very simple way and it turned out things so a lot more complicated. And it took. We never could use those cells to really solve their problems. We started out to do and the technology improved over time and so we sort of went with the technology and did different types of things over the years.

Speaker 4: And when you say different types of things over the years for the non neuroscientists listening, uh, because we do have a few non neuroscientists that, listen, my brother in law happens to be a neuroscientist, but we'll get to that later. Maybe, maybe not. What were those again? Like the basic kind of constructs that that used to be. And then now that we're looking at it this different way, now we know. So, you know, big, broad strokes. Well, first off, I think that there was a misconception that the brain could be easily understood once you, uh, you know, do, you took it apart, he knew something about the components. And then the idea was that you could put things back together in a simple way and sort of build up the reign and you understand how things like consciousness work and whatever. But the fact is we still don't understand it and it's much more complicated.

Speaker 4: So there's, are lab did a lot of sort of technical innovations over the years. We found some different types of proteins that were involved in the maintenance of the nerve cells and um, different, a different type of structure that were made by theirselves and released into the environment and stick to other cells and communicate information. So we did a lot of, a sort of small steps along the way and obviously a huge number of people in the world that work on this. And so we were just one of them, any and, and it is still a, a, a major mystery for the most part, for the most part. We don't understand exactly how the brain works, how consciousness works. Uh, it is a mystery and indeed, and what keeps us all going, I guess. Right? That's right. Um, as, as far as Alzheimer's, because I, you know, we want to get to that.

Speaker 4: When did you first start to, to kind of deal with that record with it, if you will? Um, that was actually an accident. Um, we were working, we were working actually with these cell lines that I made 50 years ago and we found that some of the secreted proteins, some of the proteins that come out of the cells which are involved in sticking cells together, we found that one of those is actually a protein that was in the source of the plaques that occur in Alzheimer's disease. And so this is the first indication that, you know, the, the, the precursor to the amyloid peptide, which is the, the major protein that cumulates in the plaques in Alzheimer's brain. Um, this was the first demonstration that it's actually released from the cell. So that led to studying the processes, how these protein is made, how it's degraded, how, what that biological roles are.

Speaker 4: Then we got over the years, we developed a bunch of essays with my wife Pam. Ah, her, her pop, her who works in our group. She, at that time was it scripts. Anyway, we developed a bunch of essays to look at a one the role of this protein, exactly what was doing. And we also got interested in how the cells are dying in the brain and so actually when the brain is being formed of like 90 percent of the nerve cells that are produced, so ultimately die and you have a very strong selection. So people really didn't know much about the cell death and that nervous system. So we try to understand that at a cellular level. So to do that we had to have an essays that um, uh, that could mimic these effect. And what I mean by an assayer is something that if you can grow these cells in petri dishes and culture and then stress, um, some way put a toxin or something like that on them, they cells will die.

Speaker 4: And then if you put a drug that's rescues the cells, the cells will live. So it's sort of a live or die. And these are the type of what we call a screening essays to, uh, um, there's both study the process of how cells die and also to try to understand and identify drugs that stop the cells from dying. And initially, um, and how long is this working because you're, what you're explaining, you know, you did the initial work all the way back when, but as far as Alzheimer's is concerned, how long have you been, uh, working on this in particular? I think the first paper that actually got us into the field was published maybe 20 years ago. Twenty years. Okay. So it's 20 years. Come in here. It to what, what did you learn from, you know, uh, sales, uh, you know, creating or, or, um, or dying or, you know, what, what initially were you learning as far as the, the drugs that worked and the drugs that didn't?

Speaker 4: Well, first off we had to make a decision that we're actually going to start looking at drugs. Okay. So that was, um, well, they kept on dying, right? So why aren't you forced into this? Let me make sure I understand. Well, we can make the cells die by putting her in conditions where they die quickly. So over a day or so, something like that. So these ask, these essays we use are just a way to make herself die in something that's associated, some physiological, something that the body normally does. And so, um, you can think of, I think our common way to look at this would be something called oxidative stress and this is why people take anti oxidants and whatever is that when cells are exposed to high levels of activated oxygen molecules, they accumulate damage proteins and these damaged proteins killed the cells.

Speaker 4: And so we can mimic that by creating a situation and a Patriot dish where the cells die by forcing the cells to make a lot of reactive oxygen. The cells, the proteins aggregate and they killed the cell. So we, this, these type of essays only take like 24 hours to do. Okay? And so during that 24 hours, we can use sort of molecular techniques to see which proteins and lipids and fatty acids and nucleic acids, the different components of the cell are changed. And so we can map out pathways by which the cells are dying in that short period of time. And we think if you look at the aging brain and either animals like mice or humans, you see that these processes are, that we can mimic in a cell culture system are very similar to what's occurs in the human brain. Interesting. As they get older, as they can, that's very critical to argument that I'll make the way we do the drug discovery process.

Speaker 4: So when, when did you actually come to the realization, okay, we are actually going to go down this path. Um, we can blame that on a really great a Postdoc, Ben Lou in the lab and he from a lab that was sent, he was interested in Sulfa himself in a sort of eternal youth. And he had figured out that he thought he had discovered a molecule as a graduate student, which actually, uh, prevented this process of oxidative stress, reactive oxygen species accumulation, this whole business of accumulating damage proteins. And so he had brought this molecule to our lab and he had a bottle of which he thought contained this particular molecule. And he was sort of keeping a secret from us, thesis advisor, whatever. So he thought he would, he would solve the problem of aging with us and it turned out that as a, so he tried it because we had these really nice as is at that point, things which are associated with aging and oxidative stress.

Speaker 4: And um, it turned out that this molecule that he had in it and the jar had degraded into something that he couldn't, it a, these things had, they were not stable and he, the label had washed all something. He didn't know exactly what it was and he could not really reproduce what he found is a graduate student unfortunately wasn't as thesis or whatever. So it was just couldn't do it. But, so he started looking around for other types of molecules and using our essays he found um, a one molecule of wood looks pretty good to something you could buy off the shelf. And then, um, we figured we got, we'd have, we started doing medicinal chemistry and we sort of took this molecule and fused with another molecule. It's turned up, which was, um, curcumin. Curcumin is an interesting story. It's a major component of Tumeric, which is a Indian spice and exhaust tastes great.

Speaker 4: That's right. And anyway, so we're a friend of mine, great Cole at Ucla. He had been working with curricula for quite a while and showed it had some effect in alzheimers mice. And so you can alzheimers mice, it's a little counterintuitive that a mouse will get Alzheimer's, but there, um, so there are two forms of Alzheimer's disease and one of them is called familial Alzheimer's disease. This is a about one percent of all cases of Alzheimer's, Caesar, the, and it's a dominant mutation, a couple of proteins that if you have this mutation, you're going to get Alzheimer's for sure. And so and so the other, that's the only one percent. That's one percent or less. I fit this is in your family, you know it by now because people have been looking for families with us for a long, long time. And that was actually one of the major breakthroughs and the Alzheimer's field is when they found these patients and identified the genes.

Speaker 4: And that's how we got into it because about the same time that we discovered that is the precursor to one of the protein is mutated, is released from cells, they, their genetics came out with his familial Alzheimer's disease. They found the gene that a sequence 10. So that was sort of our contribution was sort of coincidental with a genetic contribution. And so. So I just want to stop you because how much of you said this is by mistake and it's coincidental, but you're working real hard. Blow out while this is happening. How many, you know, how, how much of a, of this mistake or this, this coincidence is, is driven by your, your work. Why do you use those words? I think is my question because it seems like it's not coincidental to me if you're already on the path. Well, I think a lot of things in science, I mean there's, there's sort of the science progresses sort of one step at a time.

Speaker 4: It was a say. But when some things you can't predict. And so when we were working, you know, this is a very trivial example, but what we are working with these cells, looking at that, trying to figure out some molecules involved in cell adhesion and one of those turned out to be this protein, which is a major component of Alzheimer's disease. And so that something we weren't looking for exactly, but it came across it and became a. But at the same time, you know, people in other parts of the world, we're working with the genetics. And so, so, um, at that time it was a significant, you know, into a coincidence. But it's, that's the way science works, right? So, so here you are, you're, you're with this, um, this, uh, a compound that's within Tumeric, right? What was it called again? Curcumin. Curcumin, right?

Speaker 4: Um, and so that, I already loved the fact that that's plant based, right, if you will. So anyway, we from actually my wife had the same time it had been working with other plant products. So at the present time, row lab works with both her lab and my lab work quite a bit with these plants. And uh, so to isolate, you know, natural products and that sort of the basis of where we started our chemistry from. And so the idea was that curcumin, it's has some efficacy in animal models. It's um, it's a works a little bit, um, you know, removes plaques and it's been put in clinical trials for humans. Humanitas FDA approved drug for I think pancreatic cancer or something like that. It really doesn't work very well. But anyway, it's been around a long time, but it has extremely bad chemists, medicinal chemistry properties.

Speaker 4: And by that I mean it's degraded in the gut and so it doesn't really get, it doesn't even get very well out of the intestines that is hidden. The doesn't gets in, the blood is broken down and partially it does get into the brain. So it's not strong enough basically. Right. Do a good job if it could ever get there. Right. Okay. And so in the, um, now they put it in formulation, put associating with liquid, it gets a little bit better in the brain itself. But at that point we thought, well, we could make a much better curcumin basically. And so that's sort of how we started, I was maybe 15 years ago, something like that. And it's been a very slow process all along. We haven't had. It's very difficult to get funding for this type of stuff. And so we got a little private money and that really helped to push things along.

Speaker 4: And so we go over the last 15 years we've sort of improved the curcumin molecule to make it much better drug. And the way we do that is we have these essays which are associated with aging, the aging brain, and this is sort of what I alluded to earlier with one or two essays like with oxidative stress, but we have now a battery of six or eight essays that mimic different aspects of what happens in the human brain as it gets older. So our approach to drug discovery is totally different than what's used by the pharmaceutical industry, which I had been working on this Alzheimer's. I'm a problem for 20 years essentially. And they, they are approach to drug discovery I think where these diseases, where these neurodegenerative diseases is totally wrong and they. But they insist on doing everything their way or no way I guess.

Speaker 4: Well, there's people that. But let's make sure we understand what you're saying. Uh, you did explain your approach. How is their approach different? Good point. And so their approach is they want to know what's called a molecular target. So if you have a say you have a disease like Alzheimer's, that's the example we're talking about. So let's use that. You can go through any disease or many of these age associated neurodegenerative diseases. That same problem. Okay. And so what they see, so you have this one percent of the population that has Alzheimer's had habit, genetic form of Alzheimer's, and there's this one or two proteins that are involved in that. So with the major protein is this amyloid, uh, it's called amyloid precursor protein. That's a protein from which they're the small peptide, the, a Beta peptide. This, a constituent of plaques is derived. And so they drove to the companies that are standard approaches.

Speaker 4: They want a single target. So they want something that they can design a drug around so they have to pick a target. And so this was the obvious first choice and I agree with that. There's no reason not to. So basically what they did, they people, not the drug companies themselves, but they figured out how this, this peptide is made and the enzymes that make it and so, and they did two things. They designed drugs which inhibit the synthesis of that peptide cafe and the other thing they made antibodies or they had that removed the peptide from the brain basically. And so there's these two groups of molecules that have been in clinical trials for 15 years or so and they've all the clinical trials that have completely failed and so, but they're still assisting. This is the way to do it. And the reason that they liked this approach is that it simplifies their chemistry.

Speaker 4: It simplifies their way of thinking about things. And our, it's linear, it's direct and it's worked in other conditions, right? So, so vascular diseases, whatever. But the brain is just much more complicated. And these diseases of aging are much more complicated and it's not a single targets going to solve the problem. It's not a single target that's going to solve the problem. Is this also the thinking that gets us so many kinds of side effects for a, you know, if I'm taking, you know, x drug for a why issue, then I because of that linear targeted thinking be along the way of that solving that one issue here, side effect, a side b side effects. So that's a very astute observation because the argument we get, so the way we develop drugs is we start with natural products which have multiple targets and then we'd try to make them into better drugs for the medicinal chemistry and pharmaceutical point of view and but the drug, the medicinal chemists who constantly are trashing our grants applications, they has, they make the argument that, you know, unless you have a single target, then you can't predict the side effects.

Speaker 4: And that's just obviously not true. And so most of the psychoactive drugs is that the drugs that are used for those types of conditions, they have the, they don't even know how they work even though they were developing on a basis of a single target. They, they interact with a lot of different targets and they don't actually how these drugs are working, they really don't understand, but then they'll come back and use the same argument that you have to know the target here in order for them to support the development of a drug. Right. So, um, so the thinking is completely different and they insist on it their way and then kind of trashy, right? What's, what's that? They certainly do. And so what's interesting is if you look back that the drugs are actually in the clinic. I mean if you look at just the sort of the skimmer chemical skeletons of those drugs by 75, 80 percent of those are based on natural products which were developed by the type of essays that we use more than a single target approach which have developed very few drugs actually. Interesting. Okay. Alright. So there we have the two different approaches, which is I'm going to build this from here. I've got multiple targets. We'll see how it all goes that your approach

Speaker 5: versus their approach of I've got that one target. Um, you know, a damn the torpedoes, here we go. That's right. Still doing it. So, um, so, you know, getting back to a building, uh, you know, that we had, we were on a 15 year path when, when we left off, I still can't get that, a component of tumeric stuck in my head. What, what was that called again? A curcumin. Curcumin, for some reason I can't, but anyway, uh, so you're still working on curcumin. It's taking 15 years. When was the next step? When was that?

Speaker 4: Well, the next step. First you have to have the MSA. So we developed all these essays that worked really well and based on aging, since aging is by far the biggest risk factor of Alzheimer's is not the a Beta or whatever. It's not the amyloid. Lot of people have dementia, they don't have any amyloid, lot of people have, a lot of amyloid don't have dementia. So we thought aging is by far the risk factor. So fortunately we over the years has been working on these essays, so we had this battery of essays and then the next step is just to make it, as I said, into a much better drug. And so this has been done. Um, uh, Panama, her, my associated solex, she's done this with a Jewish life, has done those with the uh, um, FYSA, Tendra, flavonoid, and we've done it with a curcumin derivatives.

Speaker 4: And so then the next step you have this drug, then the next step is you want to see if it's safe. So we tested in different safety essays is pretty straightforward term. If it gets into the brain, then the idea is there, you want to get into clinic, so you have to show that it works in animal models. So we've shown that like our, our lead drug, which we call j 1:47, that works very well in multiple, like we put it in 12 different animal models for memory and Alzheimer's is each and it actually is it, it prevents aging to some extent and mice. And so we have a lot of data then then the next step, which, so we had this, a lot of this data five years ago and the next step is trying to get money to get to at the FDA drug approval process because all of the basic work was done, it was this, this drug discovery aspect and the next step is to get it, you know, trying to get an a clinic and that's incredibly difficult and fortunately we had a of so the first step, a disk for the review of the process where you have to get the toxicology died.

Speaker 4: So this is in two species, usually dogs and rats and you have to find out this is all done under the guise of called an ind, investigational new drug and you have to. This is FDA approval process and so you have to have this done by companies that are FDA approved companies and we can't do any of this work in the lab and it costs a lot of money. It costs a couple million dollars. And so it took a long time. Finally, we couldn't get money from anywhere basically to do it. And finally, one the, I'm the head of our board of trustees, Irwin Jacobs was very generous and he, he was willing to support, uh, the, this high and deep part of the process and so we got it through with that. We've spent pretty much through, it's not totally true, but it says a little more paperwork, a little bit more money required, but it's pretty, it's, we, we know the starting dose for people and was always ready to go into phase one clinical trials.

Speaker 4: Excellent. And so, um, one of the, uh, so we're still in the process of trying to raise money for that. Okay. That's it. If folks wanted to go to your website, what were the. Wherever they go, if, uh, if they wanted to donate. Well it just, it's, you'd have to go to the sulk institute. Where does, where does cannabis come into this whole thing? Okay. So that's the interesting part. So how we got into this whole thing. So it had sort of a new line of work. And so one of the things that people want to know when you have a new drug is how does it work? Sure. And so we, one of the ways that you can sort of find out what is working as you can do some screening against a known drug targets are things that are these proteins that occur in the brain that are involved in different aspects of how the brain functions.

Speaker 4: And so we did a screen with, um, with our, with j 1:47 compound and we screened, we've probably, I don't know, a thousand different possible targets and at one of these very weakly associated with the CB one receptor which cannabinoid receptor and, but it wasn't enough to really be relevant to the actual because it required much higher concentration is activate this receptor that our drug works in our essay. So, um, we, we were, um, it was a curiosity. I didn't really pay much attention to it. And then what happened was we did discover the target for a drug which happens to be a protein and sort of the structure called Mitochondria, which is sort of the energy, energy generating structure within the brain that would make, so all the ATP and all of the stuff that you're required to make things work. And so we did understood we've, and we've figured out the target, which was a major amount of work and then they deck step was, you know, once the drug interacts with the target, what goes on after that.

Speaker 4: And so, uh, we've um, we looked at a lot of different things and it turned out that, uh, that this drug interaction with our targeted, it mobilizes, it changes the calcium. Calcium is a big component of cells in the sense that it's used. It's used as a sort of transmitting signals within cells between different organelles and outside and the inside. And it's a, it's a but too much is bad, too much is bad, but the cell can regulate this. So it's got probably hundreds of molecules which actually do that. I said it turns out to the CB, one receptor is one of these molecules. So, so then, so we, we thought that this was a possibility. And so the way to test that as you do you find drugs that interact with this receptor in CFA can do the same thing is, is what your drug does.

Speaker 4: And so are comped. I shouldn't call the drug, but so thc is one of the psychoactive component of marijuana and that turns out to when we put our, our drug honest cells, that goes through a series of events and this prevents the cells from dying. And so when you do the same thing with Tac, it essentially mimics what are drugs are doing j 1:47 and 20 years to do it. Now here we go. See, boom, same thing, not the same thing. Or we know these drugs, not psychoactive. So they attended it. We think that that, that molecule somewhere, the CB one receptor or somehow involved. But I think there's a caveat to this because those are the um, so that. So that's sort of, we published a paper on this in the paper, was about more about the, how this drug is working, some of the things they're doing in cells rather than thc itself.

Speaker 4: But thc made the headlight so to speak because it was very and flag was associated with that. So that's right. And so, um, how so explain that please. Okay, so, so an interesting aspect of Alzheimer's disease which is not very widely known and appreciated. So Alzheimer's takes a long time to develop. And so it goes through a series of a sequence of events. I mean, you, things are going bad in your brain just with aging per se and a little worse with Alzheimer's. And so, so if you're going to get Alzheimer's, the first thing that happens is you, you accumulate some Hedis, a Beta peptide and inside nerve cells. And um, we think that causes an inflamed inflammation response within these cells. And so that's sort of something of a new observation because people thought that you had to have immune cells, you know, things from the immune system that to do this or a certain type of glial cell, but, but if you look at the data to this is the first step, and then what happens is you start accumulating this, this amyloid outside the cell, and once, sometime after that starts to occur, then you start to see the, the early stages of dementia.

Speaker 4: So it was called mild cognitive impairment. And so, and then a little bit after that, she started seeing this cells accumulate this, these, these tangles within cells and this, this indicates a nerve cells are starting to die. And so there's a sequence of events that we think are occurring very early on, is this accumulation within nerve cells of these proteins and then outside the cells in the form of plaques. And then you start seeing the, with the Alzheimer's pathology, classical pathology. So then the tag being applied kind of counteracted those first couple of steps. Exactly right. So we have, as we have a tissue culture essay where we can mimic that first step and I think, and so when you put thc and that, we basically removes as the cube prevents accumulation and removes the, these, these proteins from the cell. And so we haven't done this in animals yet, but that's sort of the next step would be a good step for somebody to do.

Speaker 4: And uh, um, it's something we could do. But, um, I think the ideas that there's thc is, is activating some pathway and the cells which leads to the removal of this accumulated stuff at very early stages of the disease and whether this does the same thing later in the disease, we don't know. And um, but as I say, the, we think it's through this cannabinoid receptor, but the assumption is that that's the only way that this thc is working. And um, but as we know, we were going to be exactly right. So it could be some other molecule. It's doing the trick and the cells and thc mimics either way or both ways. Uh, it would behoove us to continue as far as this, uh, uh, research. Yes. Right. No, this is. So this was sort of the interesting aspect from my perspective. Once I got into this a field we had published, this paper was at a pretty Nice, a good journal.

Speaker 4: It was a, and it got an enormous number of a media citation is like 80 right off the bat. It was the highest citadens decided media citations for I probably every 50 years, right? For sure for me probably ever had anyway. And within that, within that group or journals too, I think. And so, um, this, we were really interested us. And so we talked to the people in solitary administration. But the problem is that, you know, it was very difficult because a schedule one drug, we basically couldn't do it. We couldn't continue and to base the way we, the only reason that we could deal with this to be anywhere to get tac as we could get what's called chromatography standards. Were they very tiny amounts of the thc or these other cannabinoids. They come in a solution of hexane or Ceto Nih trial or something which is poisonous.

Speaker 4: And then being chemists, we can purify it from there, but we can only get very small amounts now, you know that with the new, uh, kind of a schedule, one was kind of reapplied to cannabis, but, um, you know, research was opened up and have you done any investigation on salt? Could be one of the say. So yes, we've done, we'd done some homework on that. I just haven't had time to fill out the paperwork. So. And want to intern for Dave wouldn't know. So I don't know how bad it is. We've had to do too much already so we can get that done probably. But so what the DA says is takes to speed it up. Normally it took six months to a year, now they go three bucks, six bucks, something like that. Add for the process. And then, uh, the problem is we can only get, we still can only get limited strains of marijuana from the Missouri or Mississippi or wherever they are.

Speaker 4: And so this is something very knowledge as to what we went through with the stem cell problem. You know, when Bush said you can only have four or five lines of stem cells this so we can only get, I don't know what the number is, but not a large number of, of marijuana strains. And so that's quite limiting and I don't know why they would make that rule. But anyway, that that's it. So our goal is we do medicinal chemistry. We'd like to purify things from plants that we think that there's a lot of people have studied these plants probably a huge amount and there's a huge amount of data out there, but they haven't really used the type of essays that we use. And so I think the trick is that the unique part of our science says we have these essays which are mimic brain aging.

Speaker 4: So I think we can pick up compounds that are quite unique and have not been looked at in the context of neurodegeneration. So that's what we'd like to do. And then there's some sort of ancillary stories that came up that sort of fun. Such as, give us one, one story which I think is great and I really appreciated is so after there was a press release, I got lots of phone calls from different people and a lot of them were by grandmother has Alzheimer's, whatever. How much should I give her marijuana and this can't do. Obviously I can't say anything I've got but we don't know anything. Basically nothing is known about Alzheimer's. That context of where water therapy. And so like you said, it's only the first couple of steps that you know that they can be good. Right. And there's so much more research agenda.

Speaker 4: If you look in the literature, there's a lot of work done on different for Parkinson, traumatic brain injury, things like that. Sure. But there's basically nothing out there with Alzheimer's. There's some papers which are okay, but it's so anyway that most of the things conversations were like that and I just said, you know, I don't, I can't make a judgment on that. Yeah. So. But one guy called me up who works in San Diego and he's a medical marijuana supplier for medical marijuana is San Diego County. And he, he does a lot of hybridization himself and so he has a mother in law, was had Alzheimer's and so he, a lot of people have been trying marijuana for Alzheimer's for years I assume. And so he's been giving it to his brother in law and so, and he said that basically they had no effect and they got this new hybrid that he said that his just had a dramatic effect on the, in law.

Speaker 4: And so the, um, I think it's mother law but some relative and so they love. Right. And so he was very enthusiastic about, you know, be looking at us and I, you know, this is what God made really more interested is because of the type of skills we have in the lab, that technology, we could compare these strain. It did work, it did work and we can see what's different. We could put it through our essays, we could put it in mice. And so this was something that we really could do. And, but then we looked into trying to do it. And this whole, initially the people there were somewhat hesitant and then they became more supportive and uh, so that's something we're trying to do, but it's still not clear we can actually do it because we get funding from the federal government and if even though I can grow it in my backyard now and previously by it from medical marijuana place, and if we brought one leaf of that into the cell, constitute it would basically they could shut the place down because it's in violation of federal law.

Speaker 4: And so I think there's some ambiguity about this at the present time was some ambiguity, his aim, is that right? Yeah, absolutely. Something I've been trying to figure out this meeting actually and talked to some people that were involved in this, but uh, anyway, so they were going to get to schedule one license. We can do that. We'll write up a little protocol and see what happens and try to keep pushing it a little bit and we go keep pushing it a little bit. That seems like 50 years. That's what you do, right? Let's see what we can do today, right?

Speaker 5: Uh, I want to thank you for your, uh, work. Obviously there is a, you know, there's a glimmering light at the end of, you know, what might be a very long or maybe even somewhat short tunnel, so engage@countyeconomy.com if you want to get in touch with Dave and so then I'll sift through, uh, you know, uh, responses and get the right ones to you. Um, my mother, uh, a personal note. My mother was sick with amyloidosis for three years and then passed away about an hour. It's 11 years ago. Um, so offline. I'm just gonna continue that conversation with you. It's not quite on subject here, right? So I will ask you the three final questions unless you had something there. No. Oh, okay. Three final questions. So I'll ask you the three final questions. I'll tell you what they are and then ask you them in order. What has most surprised you in work?

Speaker 5: We usually ask what has most surprised you in cannabis but you haven't done enough. So what has most surprised you in work? What has most surprised you in life? That's the second question. And on the soundtrack of Dave Schubert's life professor, what is one track, one song that's got to be on there? First things first, what has most surprised you in your 50 years of work? Fifty plus years of work for many 50 years or 50 years and just the way science is done now and the way science was done when I started and the difference in the, um, sort of the social aspects and the aggressiveness and this is a different type of scientific world. And it was long time ago. I see. And you, you might've liked the other one better is what I'm hearing? Yes. What about the life? What has most surprised you in life?

Speaker 5: I'm probably that somebody like trump could get elected. That's a whole different story, David. It's a whole different story. We've talked a little bit about that. And another episodes we won't, we won't bog this one down with that on the soundtrack of your life. You know, a guy from Indiana who became a surfer in southern California who became a professor of over the past 50 years, one track, one song that's got to be on there. I don't know, I like some of the old surfing movie, so it was sort of what got me going to begin with. So maybe some of the stuff, maybe that type of thing. Yeah, yeah, yeah. Dick Dale was. I mean, that's surf music. Yeah. Still to this day, but I think that's good for everybody. That's right. A professor, Dave Schubert. Thank you so much, very much. Appreciate your work. Very much. Appreciate your time. Pleasure to do it. All right. And there you have Dr Dave Schubert

Speaker 1: as well as Jamie Lowell. Way Back when. So, you know, Jamie's got a handle on what's happening in Michigan. Dave's got a handle on what's happening with Alzheimer's at least as much as he can. Fifty years of work. Uh, unbelievable. Very much appreciated the time that I had with Professor Schubert as well as with Jamie. Very much appreciate the time that you spend. Thanks so much for listening.

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